The established biomarker for hepatocellular carcinoma (HCC), serum α-fetoprotein (AFP), has suboptimal performance in early disease stages. This study aimed to develop a metabolite panel to ...differentiate early-stage HCC from cirrhosis. Cross-sectional metabolomic analyses of serum samples were performed for 53 and 47 patients with early HCC and cirrhosis, respectively, and 50 matched healthy controls. Results were validated in 82 and 80 patients with early HCC and cirrhosis, respectively. To retain a broad spectrum of metabolites, technically distinct analyses (global metabolomic profiling using gas chromatography time-of-flight mass spectrometry and targeted analyses using liquid chromatography with tandem mass spectrometry) were employed. Multivariate analyses classified distinct metabolites; logistic regression was employed to construct a prediction model for HCC diagnosis. Five metabolites (methionine, proline, ornithine, pimelylcarnitine, and octanoylcarnitine) were selected in a panel. The panel distinguished HCC from cirrhosis and normal controls, with an area under the receiver operating curve (AUC) of 0.82; this was significantly better than that of AFP (AUC: 0.75). During validation, the panel demonstrated significantly better predictability (AUC: 0.94) than did AFP (AUC: 0.78). Defects in ammonia recycling, the urea cycle, and amino acid metabolism, demonstrated on enrichment pathway analysis, may reliably distinguish HCC from cirrhosis. Compared with AFP alone, the metabolite panel substantially improved early-stage HCC detection.
Pioglitazone is class of thiazolidinediones that activates peroxisome proliferator‐activated receptors (PPARs) in adipocytes to improve glucose metabolism and insulin sensitivity and has been used as ...a treatment for type 2 diabetes. However, the underlying mechanisms of associated pioglitazone‐induced effects remain unclear. Our study aimed to investigate endogenous metabolite alterations associated with pioglitazone administration in healthy male subjects using an untargeted metabolomics approach. All subjects received 30 mg of pioglitazone once daily in the assigned sequence and period. Urine samples were collected before pioglitazone administration and for 24 h after 7 days of administration. A total of 1465 compounds were detected and filtered using a coefficient of variance below 30% and 108 metabolites were significantly altered upon pioglitazone administration via multivariate statistical analysis. Fourteen significant metabolites were identified using authentic standards and public libraries. Additionally, pathway analysis revealed that metabolites from purine and beta‐alanine metabolisms were significantly altered after pioglitazone administration. Further analysis of quantification of metabolites from purine metabolism, revealed that the xanthine/hypoxanthine and uric acid/xanthine ratios were significantly decreased at post‐dose. Pioglitazone‐dependent endogenous metabolites and metabolic ratio indicated the potential effect of pioglitazone on the activation of PPAR and fatty acid synthesis. Additional studies involving patients are required to validate these findings.
An unprecedented approach to the generation of an N-centered radical via a photocatalytic energy-transfer process from readily available heterocyclic precursors is reported, which is distinctive of ...the previous electron transfer approaches. In combination with singlet oxygen, the in-situ-generated nitrogen radical from the oxadiazoline substrate in the presence of fac-Ir(ppy)3 undergoes a selective ipso addition to arenes to furnish remotely double-functionalized spiro-azalactam products. The mechanistic studies provide compelling evidence that the catalytic cycle selects the energy-transfer pathway. A concurrent activation of molecular oxygen to generate singlet oxygen by energy transfer is also rationalized. Furthermore, the occurrence of the electron transfer phenomenon is excluded on the basis of the negative driving forces for one-electron transfer between oxadiazoline and the excited state of fac-Ir(ppy)3 with a consideration of their redox potentials. The necessity of singlet oxygen as well as the photoactivated oxadiazoline substrate is clearly supported by a series of controlled experiments. Density functional studies have also been carried out to support these observations. The scope of substrates is explored by synthesizing diversely functionalized cyclohexadienone moieties in view of their utility in complex organic syntheses and as potential targets in pharmacology.
Memory stabilization after learning requires translational and transcriptional regulations in the brain, yet the temporal molecular changes that occur after learning have not been explored at the ...genomic scale. We used ribosome profiling and RNA sequencing to quantify the translational status and transcript levels in the mouse hippocampus after contextual fear conditioning. We revealed three types of repressive regulations: translational suppression of ribosomal protein-coding genes in the hippocampus, learning-induced early translational repression of specific genes, and late persistent suppression of a subset of genes via inhibition of estrogen receptor 1 (ESR1/ERα) signaling. In behavioral analyses, overexpressing Nrsn1, one of the newly identified genes undergoing rapid translational repression, or activating ESR1 in the hippocampus impaired memory formation. Collectively, this study unveils the yet-unappreciated importance of gene repression mechanisms for memory formation.
Vutiglabridin, which affects the pharmacokinetics (PKs) of food, is currently under clinical development for the treatment of obesity. This study aimed to evaluate the effects of low‐ and high‐fat ...meals on PKs of vutiglabridin in healthy male subjects. A randomized, open‐label, single‐dose, three‐period, six‐sequence crossover study was conducted. The subjects received a single oral dose of vutiglabridin 480 mg in a fasted state, 30 min after the intake of a low‐fat meal (total 500–600 kcal, fat content 100–125 kcal) and high‐fat meal (total 800–1000 kcal, fat content 500–600 kcal), with a 21‐day washout period. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve to the last measurable timepoint (AUClast) were calculated. After intake of low‐ and high‐fat meals, systemic exposure to vutiglabridin was increased, and the time to reach Cmax (Tmax) was delayed compared to that in the fasted state. The GMRs (90% CIs) of low‐fat meal to fasted state for Cmax and AUClast were 2.14 (1.76–2.60) and 2.15 (1.92–2.42), respectively, and those of high‐fat meal to fasted state were 3.07 (2.53–3.72) and 3.00 (2.67–3.37), respectively. The median Tmax was delayed by 1.5 h in both fed states compared with that in the fasted state. The study drug was well‐tolerated after administration in both the fed and fasted states. Food ingestion substantially increased the extent of oral vutiglabridin absorption in healthy subjects, and this enhancement increased with the fat content of the meal.
Reductive N–O bond cleavage has been widely explored for providing either N or O radical species for various coupling processes. Despite significant advances, this photoredox pathway is less ...appealing due to poor atom economy owing to the loss of one fragment during the transformation. In this regard, the homolytic N–O bond cleavage by an energy-transfer pathway to provide two key radicals would be highly desirable for overcoming the limitations of the use of one fragment. We report an exclusive energy-transfer approach for the development of a challenging radical–radical C(sp3)–N cross-coupling process by reactivity-tuning of the catalytic system. The homolytic N–O bond cleavage of oxime esters in the presence of an Ir complex produces acyloxy and iminyl radicals, which undergo decarboxylative cross-coupling to yield valuable imines (typically 0.25 mol % cat. and 1 h reaction time). Extensive photophysical and electrochemical measurements, as well as density functional theory studies, were carried out to probe the mechanism and the operation of a Dexter-type energy-transfer pathway was revealed. The choice of solvent (EtOAc) and reaction concentration were critical for achieving the selectivity and reactivity in this cross-coupling process. The synthetic utility of this method was explored by studying highly functionalized oxime esters, including derivatives of biologically active natural products and drug molecules. Furthermore, in situ transformations of the imine products into pharmaceutically important amines were also demonstrated, showcasing the utility of the imine products as valuable amine building blocks.
Objective
We evaluated the efficacy of endovascular thrombectomy (EVT) on the functional outcome of patients with acute basilar artery occlusion and low posterior circulation acute stroke prognosis ...early computed tomography score (PC‐ASPECTS).
Methods
We identified patients with acute ischemic stroke due to basilar artery occlusion and PC‐ASPECTS of 6 or less, presenting within 24 h between August 2008 and April 2022. The primary outcome was a favorable functional outcome, defined as a modified Rankin Scale (mRS) score of 0–3 at 90 days. The secondary outcomes included an mRS score of 0–2, a favorable shift in the ordinal mRS scale, the occurrence of symptomatic intracranial hemorrhage (sICH), and mortality at 90 days. We compared the outcome of patients treated with EVT and those without EVT, using the inverse probability of treatment weighting methods.
Results
Out of 566 patients, 55.5% received EVT. In the EVT group, 106 (33.8%) achieved favorable outcomes, compared to 56 patients (22.2%) in the conservative group. EVT significantly increased the likelihood of achieving a favorable outcome compared to conservative treatment (relative risk RR 1.39, 95% confidence interval CI, 1.11–1.74, p = 0.004). EVT was associated with a favorable shift in the mRS (RR 1.85, 95% CI, 1.49–2.29, p < 0.001) and reduced mortality without an increase in the risk of sICH. It did not have an impact on achieving an mRS score of 0–2.
Interpretation
Patients with acute basilar artery occlusion and a PC‐ASPECTS of 6 or less might benefit from EVT without an increasing sICH. ANN NEUROL 2024;95:788–799
Ursodeoxycholic acid (UDCA) is a metabolic by-product of intestinal bacteria, showing hepatoprotective effects. However, its underlying molecular mechanisms remain unclear. The purpose of this study ...was to elucidate the action mechanisms underlying the protective effects of UDCA and vitamin E against liver dysfunction using metabolomics and metagenomic analysis. In this study, we analysed blood and urine samples from patients with obesity and liver dysfunction. Nine patients were randomly assigned to receive UDCA (300 mg twice daily), and 10 subjects received vitamin E (400 IU twice daily) for 8 weeks. UDCA significantly improved the liver function scores after 4 weeks of treatment and effectively reduced hepatic deoxycholic acid and serum microRNA-122 levels. To better understand its protective mechanism, a global metabolomics study was conducted, and we found that UDCA regulated uremic toxins (hippuric acid, p-cresol sulphate, and indole-derived metabolites), antioxidants (ascorbate sulphate and N-acetyl-L-cysteine), and the phenylalanine/tyrosine pathway. Furthermore, microbiome involvement, particularly of Lactobacillus and Bifidobacterium, was demonstrated through metagenomic analysis of bacteria-derived extracellular vesicles. Meanwhile, vitamin E treatment did not result in such alterations, except that it reduced uremic toxins and liver dysfunction. Our findings suggested that both treatments were effective in improving liver function, albeit via different mechanisms.
Recent studies found that short-chain fatty acids (SCFAs), which are produced through bacterial fermentation in the gastrointestinal tract, have oncoprotective effects against cervical cancer. The ...most common SCFAs that are well known include acetic acid, butyric acid, and propionic acid, among which propionic acid (PA) has been reported to induce apoptosis in HeLa cells. However, the mechanism in which SCFAs suppress HeLa cell viability remain poorly understood. Our study aims to provide a more detailed look into the mechanism of PA in HeLa cells. Flow cytometry analysis revealed that PA induces reactive oxygen species (ROS), leading to the dysfunction of the mitochondrial membrane. Moreover, PA inhibits NF-κB and AKT/mTOR signaling pathways and induces LC3B protein levels, resulting in autophagy. PA also increased the sub-G1 cell population that is characteristic of cell death. Therefore, the results of this study propose that PA inhibits HeLa cell viability through a mechanism mediated by the induction of autophagy. The study also suggests a new approach for cervical cancer therapeutics.
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